Development of EDTA Crosslinked Beta-Cyclodextrin for Use in Drug-Eluting Cardiovascular Stents

Drug-eluting stents (DES) reduce the occurrence of in-stent restenosis in patients who have a stent placed in cardiac arteries. However, current DES do not have a long enough window of drug release to prevent late in-stent restenosis. Beta-cyclodextrin (BCD), a polymer which is capable of drug elution, has a high biocompatibility, and is able to be refilled with drug, is polymerized using Ethylenediaminetetraacetic acid (EDTA). The EDTA-BCD polymer particles have shown good attachment on Cobalt Chromium cardiovascular stents through imaging with SEM and analysis with EDS. Drug release studies done on the particles have shown extended drug release, showing that EDTA-BCD polymers have the capability of being a refillable and biocompatible coating for cardiovascular stents that can reduce the occurrence of late in-stent restenosis

Development of EDTA Crosslinked Beta-Cyclodextrin for Use in Drug-Eluting Cardiovascular Stents

Drug-eluting stents (DES) reduce the occurrence of in-stent restenosis in patients who have a stent placed in cardiac arteries. However, current DES do not have a long enough window of drug release to prevent late in-stent restenosis. Beta-cyclodextrin (BCD), a polymer which is capable of drug elution, has a high biocompatibility, and is able to be refilled with drug, is polymerized using Ethylenediaminetetraacetic acid (EDTA). The EDTA-BCD polymer particles have shown good attachment on Cobalt Chromium cardiovascular stents through imaging with SEM and analysis with EDS. Drug release studies done on the particles have shown extended drug release, showing that EDTA-BCD polymers have the capability of being a refillable and biocompatible coating for cardiovascular stents that can reduce the occurrence of late in-stent restenosis

Pseudopolyrotaxane Formation in the Synthesis of Cyclodextrin Polymers: Effects on Drug Delivery, Mechanics, and Cell Compatibility

Numerous groups have reported the use of cyclodextrin (CD)-based polymers for drug delivery applications due to their capacity to form inclusions with small molecule drugs, delaying the rate of drug release beyond that of diffusion alone (termed “affinity-based” drug delivery). Herein we demonstrate synthesis and characterization of a new family of CD-based polymers, some as pseudopolyrotaxanes, generated under mild (aqueous, room temperature) conditions. The formation of these new affinity polymers results in broad mechanical properties. Three diglycidylether cross-linkers which vary in length from 0 to 10 ethylene glycol units were examined. Pseudopolyrotaxane formation was found only with the highest-length cross-linker, noted first by a sharp change in both material properties and then confirmed by chemical signature. Materials were thoroughly evaluated by NMR, DSC, DMA, TGA, XRD, and FTIR. Cross-linker choice was also tested for impact on drug loading and delivery capacity, using antibiotics as model drugs. Chemically similar polymers without showing affinity rapidly saturated in loading experiments, while affinity materials showing high capacity for drug loading, even beyond the solubility limit of the drugs. When using the polymers with these new cross-linkers, affinity-based drug delivery is maintained: the materials are capable of antibiotic delivery, and clearance of Staphylococcus aureus, at least an order of magnitude better than diffusion-only control polymers. In cell compatibility studies, CD-based polymers were shown to have low overt cell toxicity and even resisted cell adhesion, presumably due to their highly hydrated state

Elucidating the Structure-Function Relationship of Solvent and Cross-Linker on Affinity-Based Release from Cyclodextrin Hydrogels

Minocycline (MNC) is a tetracycline antibiotic capable of associating with cyclodextrin (CD), and it is a frontline drug for many instances of implant infection. Due to its broad-spectrum activity and long half-life, MNC represents an ideal drug for localized delivery; however, classic polymer formulations, particularly hydrogels, result in biphasic release less suitable for sustained anti-microbial action. A polymer delivery system capable of sustained, steady drug delivery rates poses an attractive target to maximize the antimicrobial activity of MNC. Here, we formed insoluble hydrogels of polymerized CD (pCD) with a range of crosslinking densities, and then assessed loading, release, and antimicrobial activity of MNC. MNC loads between 5–12 wt % and releases from pCD hydrogels for >14 days. pCD loaded with MNC shows extended antimicrobial activity against S. aureus for >40 days and E. coli for >70 days. We evaluated a range of water/ethanol blends to test our hypothesis that solvent polarity will impact drug-CD association as a function of hydrogel swelling and crosslinking. Increased polymer crosslinking and decreased solvent polarity both reduced MNC loading, but solvent polarity showed a dramatic reduction independent of hydrogel swelling. Due to its high solubility and excellent delivery profile, MNC represents a unique drug to probe the structure-function relationship between drug, affinity group, and polymer crosslinking ratio

Grafting of Short Elastin-Like Peptides Using an Electric Field

Surface-grafted elastin has found a wide range of uses such as sensing, tissue engineering and capture/release applications because of its ability to undergo stimuli-responsive phase transition. While various methods exist to control surface grafting in general, it is still difficult to control orientation as attachment occurs. This study investigates using an electric field as a new approach to control the surface-grafting of short elastin-like polypeptide (ELP). Characterization of ELP grafting to gold via quartz crystal microbalance with dissipation, atomic force microscopy and temperature ramping experiments revealed that the charge/hydrophobicity of the peptides, rearrangement kinetics and an applied electric field impacted the grafted morphology of ELP. Specifically, an ELP with a negative charge on the opposite end of the surface-binding moiety assembled in a more upright orientation, and a sufficient electric field pushed the charge away from the surface compared to when the same peptide was assembled in no electric field. In addition, this study demonstrated that assembling charged ELP in an applied electric field impacts transition behavior. Overall, this study reveals new strategies for achieving desirable and predictable surface properties of surface-bound ELP

Poly(methyl methacrylate) Bone Cement Composite Can Be Refilled with Antibiotics after Implantation in Femur or Soft Tissue

While periprosthetic joint infections (PJIs) result in a small percentage of patients following arthroplasties, they are challenging to treat if they spread into bone and soft tissue. Treatment involves delivering antibiotics using poly(methyl methacrylate) (PMMA) bone cement. However, antibiotic release is insufficient for prolonged infections. Previous work demonstrated efficacy of incorporating insoluble cyclodextrin (CD) microparticles into PMMA to improve antibiotic release and allow for post-implantation drug refilling to occur in a tissue-mimicking model. To simulate how antibiotic refilling may be possible in more physiologically relevant models, this work investigated development of bone and muscle refilling models. The bone refilling model involved embedding PMMA-CD into rabbit femur and administering antibiotic via intraosseous infusion. Muscle tissue refilling model involved implanting PMMA-CD beads in bovine muscle tissue and administering antibiotic via tissue injection. Duration of antimicrobial activity of refilled PMMA-CD was evaluated. PMMA-CD composite in bone and muscle tissue models was capable of being refilled with antibiotics and resulted in prolonged antimicrobial activity. PMMA-CD provided sustained and on-demand antimicrobial activity without removal of implant if infection develops. Intraosseous infusion appeared to be a viable technique to enable refilling of PMMA-CD after implantation in bone, reporting for the first time the ability to refill PMMA in bone

Injectable Extracellular Matrix Microparticles Promote Heart Regeneration in Mice with Post-ischemic Heart Injury

Ischemic heart injury causes permanent cardiomyocyte loss and fibrosis impairing cardiac function. Tissue derived biomaterials have shown promise as an injectable treatment for the post-ischemic heart. Specifically, decellularized extracellular matrix (dECM) is a protein rich suspension that forms a therapeutic hydrogel once injected and improves the heart post-injury response in rodents and pig models. Current dECM-derived biomaterials are delivered to the heart as a liquid dECM hydrogel precursor or colloidal suspension, which gels over several minutes. To increase the functionality of the dECM therapy, an injectable solid dECM microparticle formulation derived from heart tissue to control sizing and extend stability in aqueous conditions is developed. When delivered into the infarcted mouse heart, these dECM microparticles protect cardiac function promote vessel density and reduce left ventricular remodeling by sustained delivery of biomolecules. Longer retention, higher stiffness, and slower protein release of dECM microparticles are noted compared to liquid dECM hydrogel precursor. In addition, the dECM microparticle can be developed as a platform for macromolecule delivery. Together, the results suggest that dECM microparticles can be developed as a modular therapy for heart injury

Resveratrol Delivery from Implanted Cyclodextrin Polymers Provides Sustained Antioxidant Effect on Implanted Neural Probes

Intracortical microelectrodes are valuable tools used to study and treat neurological diseases. Due in large part to the oxidative stress and inflammatory response occurring after electrode implantation, the signal quality of these electrodes decreases over time. To alleviate this response, resveratrol, a natural antioxidant which elicits neuroprotective effects through reduction of oxidative stress, was utilized. This work compares traditional systemic delivery of resveratrol to the novel cyclodextrin polymer (pCD) local delivery approach presented herein, both in vitro and in vivo. The pCD displayed an extended resveratrol release for 100 days, as well as 60 days of free radical scavenging activity in vitro. In vivo results indicated that our pCD delivery system successfully delivered resveratrol to the brain with a sustained release for the entire short-duration study (up to 7 days). Interestingly, significantly greater concentrations of resveratrol metabolites were found at the intracortical probe implantation site compared to the systemic administration of resveratrol. Together, our pilot results provide support for the possibility of improving the delivery of resveratrol in an attempt to stabilize long-term neural interfacing applications